patient-reported neuropsychiatric outcomes of long-term ......immunotherapy (cd19 car t cells) has...
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Biol Blood Marrow Transplant 26 (2020) 34�43
Biology of Blood andMarrow Transplantationjournal homepage: www.bbmt.org
Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivorsafter Chimeric Antigen Receptor T Cell Therapy
Julia Ruark1, Erin Mullane2, Nancy Cleary2, Ana Cordeiro2,3, Evandro D. Bezerra4, Vicky Wu5,Jenna Voutsinas5, Bronwen E. Shaw6, Kathryn E. Flynn6, Stephanie J. Lee2,4, Cameron J. Turtle2,4,7,David G. Maloney2,4,7, Jesse R. Fann1, Merav Bar2,4,*1 Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington2 Clinical Research division, Fred Hutchinson Cancer Research Center, Seattle, Washington3 Public Health division, Fred Hutchinson Cancer Research Center, Seattle, Washington4 Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Research Center, Seattle, Washington5 Department of Medicine, University of Washington, Seattle, Washington6 Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin7 Centro Paulista de Oncologia, Sao Paulo, Brazil
Article history:Received 1 August 2019Accepted 29 September 2019
Financial disclosure: See Acknowled*Correspondence and reprint req
Cancer Research Center, PO Box 1902E-mail address:mbar@fredhutch
https://doi.org/10.1016/j.bbmt.20191083-8791/© 2019 American Society
A B S T R A C TCD19-targeted chimeric antigen receptor (CAR) modified T cell immunotherapy is a novel treatment with promisingresults in patients with relapsed/refractory lymphoid malignancies. CAR T cell therapy has known early toxicities ofcytokine release syndrome and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects.We have used patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System(PROMIS) measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia 1 to 5 yearsafter treatment with CD19-targeted CAR T cells. Mean T scores of PROMIS domains of global mental health, globalphysical health, social function, anxiety, depression, fatigue, pain, and sleep disturbance were not clinically meaning-fully different from the mean in the general US population. However, 19 patients (47.5%) reported at least 1 cognitivedifficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored �40 in global mentalhealth, indicating at least 1 standard deviation worse than the general population mean. Younger age was associatedwith worse long-term global mental health (P = .02), anxiety (P = .001), and depression (P= .01). Anxiety before CAR Tcell therapy was associated with increased likelihood of anxiety after CAR T cell therapy (P = .001). Fifteen patients(37.5%) reported cognitive difficulties after CAR T cell therapy. Depression before CAR T cell therapy was statisticallysignificantly associated with higher likelihood of self-reported post-CAR T cognitive difficulties (P = .02), and there wasa trend for an association between acute neurotoxicity and self-reported post-CAR T cognitive difficulties (P = .08).Having more post-CAR T cognitive difficulties was associated with worse global mental health and global physicalhealth. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR T celltherapy. However, nearly 50% of patients in the cohort reported at least 1 clinically meaningful negative neuropsychi-atric outcome (anxiety, depression, or cognitive difficulty), indicating that a significant number of patients would likelybenefit from mental health services following CAR T cell therapy. Younger age, pre-CAR T anxiety or depression, andacute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Largerstudies are needed to confirm these findings.
© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Key Words:
CD19-targeted CAR T cellsLate eventsPatient-reported outcomesgments on page 42.uests: Merav Bar, MD, Fred Hutchinson4, Seattle, WA 98109-1024..org (M. Bar).
.09.037for Transplantation and Cellular Therapy. Published by Elsevier Inc.
INTRODUCTIONCD19-targeted chimeric antigen receptor modified T-cell
immunotherapy (CD19 CAR T cells) has shown excellent anti-tumor activity in patients with relapsed/refractory acute lym-phoblastic leukemia (ALL) [1] and non-Hodgkin lymphoma
(NHL) [2,3], which led to the approval of tisagenlecleucel(Kymriah, Novartis; New Jersey, USA) and axicabtagene cilo-leucel (Yescarta, (Kite (A Gilead Company); Santa Monica, CA,USA) by regulatory agencies in the United States, Europe, Can-ada, Japan, and Australia. This approval has transformed thecare of patients with relapsed/refractory ALL and aggressive Bcell NHL [4-6].
At the Fred Hutchinson Cancer Research Center (FHCRC), aphase I/II clinical trial using CD19 CAR T cells demonstrated
J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43 35
high response rates in patients with relapsed/refractory ALL(85% of patients achieved minimal residual disease (MRD)-negative complete remission), NHL (51% overall response rate(ORR); 40% complete response (CR)), and chronic lymphocyticleukemia (CLL) (74% ORR; 21% CR) [7-9].
CD19 CAR T cells cause unique early toxicities, such as cyto-kine release syndrome (CRS) [10-14] and acute neurotoxicity[15,16]. CRS is a systemic inflammatory response that ariseswithin several days of the CAR T infusion and may manifest asfever, hypotension, capillary leak syndrome, and multiorgan fail-ure. Severe CRSmay affect 10% to 40% of patients [17]. Acute neu-rotoxicity can manifest as a multitude of different neurologicadverse events, including but not limited to confusion, expressiveaphasia, obtundation, myoclonus, and seizure. Severe neurotox-icity may affect 10% to 40% of patients [17]. CAR T cell product,CAR T cell dose, and patients’ characteristics (such as diseasetreated, disease burden, or prior neurologic conditions) mayaffect rates and manifestations of CRS and neurotoxicity. CRS andneurotoxicity can be fatal, but with appropriate monitoring andtreatment, they typically resolve within days to a couple of weeksafter CAR T cell infusion [17]. However, potential long-term neu-ropsychiatric adverse effects of CAR T cells as well as CRS andacute neurotoxicity are still not fully elucidated [18].
Until recently, the only cellular therapy modality for thetreatment of hematologic malignancies had been allogeneichematopoietic cell transplantation (HCT), which providesimmune response against tumor cells derived by alloreactivedonor cells but with the risk of acute and chronic graft-versus-host disease (GVHD) as well as other late effects that adverselyaffect morbidity, mortality, and quality of life of transplant sur-vivors, including significant neuropsychiatric effects [19]. Atthis time, only limited data are available regarding the long-term effects of CAR T cell therapy [18]. Thus, it is important toevaluate the late neuropsychiatric effects of CAR T and evalu-ate their effect on survivors’ quality of life.
Patient-reported outcomes (PROs), a method of measuringhealth status directly from the patient without clinician inter-pretation, have been demonstrated to be a reliable tool for eval-uation of treatment-related toxicities [20-22]. A number ofstudies have used PROs to evaluate symptoms in patients withcancer [23-25] and functional deficits and late effects after HCT[26,27]. In addition, PROs have been used to evaluate outcomesand quality of life after treatment with immune checkpointinhibitors [28,29]. These studies reveal that patient-reportedglobal health status and quality of life were better amongpatients treated with immune checkpoint inhibitors comparedto patients treated with standard chemotherapy [29-33].Recently there has been interest in incorporating PROs for evalu-ation of patients after CAR T cell therapy [34]. Standardized PROmeasurement systems, such as the Patient-Reported OutcomesMeasurement Information System (PROMIS), allow comparisonsacross patients with different diseases and treatment histories.PROMIS uses modern psychometric theory to standardize PROassessment for use in both clinical research and health caredelivery settings, including oncology settings [24,35-37]. A keyfeature of PROMIS is that scores are not disease or treatmentspecific and thus are applicable for use in settings where multi-ple different diseases and treatment histories may be repre-sented in the patient population. Thus, we have incorporatedPROs, including PROMIS measures for evaluation of symptomsand function of long-term survivors after CAR T cell therapy.
The aim of this study was to use PROs to evaluate the fre-quency and potential risk factors for adverse neuropsychiatricand other patient-reported outcomes in long-term survivorsof CAR T cell therapy.
PATIENTS ANDMETHODSStudy Population
The study cohort included 40 patients with relapsed/refractory ALL, NHL, orCLL treated with CD19-targeted CAR T cells on a phase I/II clinical trial(NCT01865617) between December 2013 and February 2018 and survived atleast 12 months after treatment (in remission or with disease progression). Thestudy was approved by the FHCRC Institutional Review Board, and all patientsprovided informed consent for treatment and for long-term follow-up.
Clinical DataClinical and sociodemographic variables were abstracted from each
patient’s chart. These included age, sex, race, employment status, marital sta-tus, medical and psychiatric history, date of CAR T cell infusion, CRS gradingbased on the Lee et al. [10] criteria, and acute neurotoxicity grading based onthe National Cancer Institute Common Toxicity Criteria for Adverse Eventsversion 4.03.
All patients underwent evaluation before CAR T cell therapy, includingsocial and psychiatric history. Most patients also underwent standardizedmental health screening by a clinical social worker using validated instru-ments (e.g., the 2- or 9-item Patient Health Questionnaire [PHQ-2/9], the 2-or 7-item Generalized Anxiety Disorder scale [GAD-2/7]) [38-41]. Severalpatients underwent additional evaluations by a consulting psychiatrist orpsychologist.
Pre-CAR T (current or history of) depression was defined as having any ofthe following: (1) PHQ-2 �3, (2) PHQ-9 �10, (3) a charted diagnosis of adepressive disorder (major depressive disorder, mixed depression and anxi-ety, adjustment disorder with depression), or (4) prescribed antidepressantmedication before CAR T cell therapy. Pre-CAR T anxiety was defined by hav-ing any of the following: (1) GAD-2 �3, (2) GAD-7 �10, (3) charted diagnosisof an anxiety disorder, or (4) prescribed anxiolytic medications that wereclearly listed for treatment of anxiety. All patients on an antidepressant had acharted diagnosis of anxiety, depression, or both and so were categorizedunder the appropriate diagnosis. Baseline sleep disturbance was determinedby either a charted diagnosis of insomnia or a charted prescription for a med-ication that was being used to treat sleep disturbance.
Assessments and MeasuresA link to an online questionnaire was emailed to patients who were at
least 1 year after CAR T cell therapy and at §2 months of their yearly anniver-sary of T cell infusion between October 2018 through February 2019; ifrequested by the patient, a paper form questionnaire was sent.
The questionnaire included the PROMIS Scale v1.2 Global Health and thePROMIS-29 Profile v2.1, as well as 30 additional questions, including 4 ques-tions pertaining to cognitive function. PROMIS-Global Health is an overallevaluation of physical and mental health consisting of 10 items and scored asa global physical health component and a global mental health component.PROMIS-29 contains 7 domains, each 4-item short forms, assessing depres-sion, anxiety, physical function, pain interference, fatigue, sleep disturbance,and ability to participate in social roles and activities, plus 1 item assessingpain intensity. Symptom domains (depression, anxiety, fatigue, sleep distur-bance, pain) were assessed in the past 7 days. There were no time restrictionsfor function domains. Additional questions included demographic data, can-cer disease status, additional diagnoses and symptoms that patients mayhave developed since CAR T cell therapy, current medications, and evaluationof cognitive functioning. Cognitive functioning was assessed by questions wedeveloped that asked if patients had experienced difficulties with concentra-tion, finding words, memory, or solving problems since their CAR T cell ther-apy; an answer of “yes” to each of those 4 questions received 1 point todetermine the total cognitive difficulty score (0 to 4).
The PROMIS measures were scored using the HealthMeasures ScoringService (https://www.assessmentcenter.net/ac_scoringservice). Raw scoreswere converted to standardized T scores that can be compared with norma-tive data from the US general population. T-score distributions are standard-ized such that a score of 50 points represents the mean for the US generalpopulation, and the standard deviation around that mean is 10 points. Ahigher PROMIS T score indicates more of the concept being measured. Forsymptom measures such as anxiety, depression, sleep disturbance, pain, andfatigue, a higher score indicates worse symptoms (e.g., a T score of 60 indi-cates 1 standard deviation increased anxiety compared with the mean for theUS general population, and a score of 40 indicates 1 standard deviation lessanxiety than the general population). For functional domains, includingglobal mental and physical health, social function, and physical function, ahigher score indicates better function (e.g., a T score of 60 indicates 1 stan-dard deviation better mental health function than the average for the generalUS population, and a T score of 40 indicates 1 standard deviation worse men-tal health function compared with the average for the general US population)(PROMIS, 2015: https://www.assessmentcenter.net/documents/PROMIS Pro-file Scoring Manual.pdf). Clinically meaningful difference was defined as halfof a standard deviation (a 5-point difference in T score) [23,26,42].
Table 1Demographic and Clinical Characteristics (N = 40)
Variable Value
Demographic
Age at time of CAR T cell therapy, yr
Median (SD) 54 (11.9)
Range 22.0-74.0
Age at questionnaire completion
Median (SD) 57 (11.7)
Range 26.0-76.0
Years after CAR T cell therapy,median (range)
3 (1-5)
Sex
Male 25 (62.5)
Female 15 (37.5)
Race
American Indian/Alaska Native 1 (2.5)
Asian 3 (7.5)
Asian, white 1 (2.5)
White 33 (82.5)
Unknown 2 (5.0)
Marital status
Married 31 (77.5)
Single/divorced/widowed 9 (22.5)
Employment status at timeof questionnaire completion
Working 17 (42.6)
Unable to work due to health 11 (27.5)
Not working but not due to health 12 (30.0)
Medical
Diagnosis
ALL 11 (27.5)
CLL 15 (37.5)
NHL 14 (35.0)
Number of prior lines of therapy
Median (SD) 5 (1.9)
Range 1-10
Prior HCT before CAR T
Autologous (auto) 4 (10.0)
Allogeneic (allo) 11 (27.5)
Auto and allo 2 (5.0)
No HCT 19 (47.5)
Prior radiation before CAR T
Local radiation (no cranial) 7 (17.5)
Total body irradiation (low dose; �4 Gy) 7 (17.5)
Total body irradiation(high dose; �12 Gy)
3 (7.5)
CNS disease involvement at any timebefore CAR T cell therapy
No 34 (85.0)
Yes 6 (15.0)
CNS-directed chemotherapy (as treatmentfor CNS involvement or prophylaxis)
No 26 (65.0)
Yes 14 (35.0)
Maximum cytokine release syndromegrade
0 6 (15.0)
1 12 (30.0)
2 16 (40.0)
3 4 (10.0)
4 2 (5.0)
(continued)
36 J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43
Statistical MethodsBaseline demographics, clinical characteristics, and PROMIS measures
were summarized by medians or means with standard deviation and rangefor continuous variables and numbers and proportions for categorical varia-bles. The strength of association between PROMIS scores was evaluated bySpearman correlation coefficients (r). To show the trends in PROMIS scoresby the number of cognitive difficulties, we used box plots and calculatedP values using linear regression, treating cognitive difficulties as a continuousmeasure. Histograms were generated for each of the PROMIS T scores toshow the sample distribution, and 2-sided P values were calculated by a1-sample t test to compare our sample to the US general population’s T scoremean of 50. Univariate analyses were conducted on the neuropsychiatric out-comes of particular interest. Linear regression was used to analyze continu-ous scores (PROMIS global mental health, PROMIS global physical health,PROMIS anxiety, PROMIS depression), and logistic regression was used toanalyze cognitive difficulties (any versus none). Depression or anxiety thatwas diagnosed before CAR T cell therapy (pre-CAR T depression or pre-CAR Tanxiety) was included in the models to adjust for a baseline effect if appropri-ate. Multivariate analyses were performed on selected outcomes using step-wise selection, with a Pvalue threshold of less than .10 for model entry andexit. All variables in the univariate analyses were included in the multivari-able selection process, and the threshold of .10 guaranteed inclusion of allvariables with a Pvalue <.10 in the model [7,43]. Due to the limited samplesize and the nature of exploratory analysis, multiplicity adjustments werenot considered. All analyses were conducted using R, version 3.4.1.
RESULTSQuestionnaire Response Rate
Between October 2018 and February 2019, 38 patientswere emailed a link to the electronic questionnaire and 14patients were provided a hard copy of the questionnaire (pertheir request or due to inability to contact patients via email).As of February 28, 2019, 40 questionnaires had been returnedand included in the analysis (29 of 38 electronic questionnairesand 11 of 14 hard-copy questionnaires, for a total responserate of 76.9%).
Patient CharacteristicsThe median (SD) age of the patients in the study cohort was
54 (11.9) years (range, 22 to 74) at the time of CAR T cell ther-apy and 57 (11.7) years (range, 26 to 76) at the time of ques-tionnaire completion. The majority was male (62.5%), white(82.5%), and married (77.5%). Patients received CAR T cell ther-apy for NHL (35%), CLL (37.5%), and ALL (27.5%). Median linesof treatment before CAR T were 5 (range, 1 to 10). Six patients(15%) had a history of central nervous system involvement atany time during the disease course before CAR T cell therapy,and 14 patients (35%) received directed central nervous sys-tem chemotherapy as treatment or prophylaxis. The majorityof patients had maximum CRS grade 1 (30%) or 2 (40%), andthe majority of patients did not have acute neurotoxicity(62.5%). Four patients (10%) had maximum grade 3 CRS and4 patients (10%) had maximum grade 3 neurotoxicity. Twopatients (5%) had maximum grade 4 CRS and 2 patients (5%)had maximum grade 4 neurotoxicity (1 of those patients hadboth grade 4 CRS and grade 4 neurotoxicity). The median timefrom CAR T cell therapy to questionnaire completion was3 years (range, 1 to 5). Twenty-three patients (57.5%) receivedadditional treatment(s) after CAR T cell therapy (including 12allogeneic hematopoietic cell transplantations [HCTs], given asconsolidation or salvage), and 33 patients (82.5%) were inremission at the time of questionnaire completion. Character-istics of the cohort are shown in Table 1.
Psychiatric History before CAR T Cell TherapyTwelve (30%) patients met our criteria for pre-CAR T
depression, 17 (42.5%) met our criteria for pre-CAR T anxiety,and 18 (45%) met criteria for pre-CAR T sleep disturbance.Immediately before CAR T therapy, 8 (20%) of the patients
Table 1 (Continued)
Variable Value
Maximum neurotoxicity grade
0 25 (62.5)
1 1 (2.5)
2 8 (20.0)
3 4 (10.0)
4 2 (5.0)
Additional treatment after CAR T celltherapy*
No 17 (42.5)
Yes
Allo HCT 12 (30.0)
Targeted therapy 12 (30.0)
Local radiation (no cranial) 2 (5.0)
CAR T cell therapy 2 (5.0)
Checkpoint inhibitors 1 (2.5)
Remission status at time of questionnairecompletion
In remission 33 (82.5)
Not in remission 7 (17.5)
Pre-CAR T psychiatric problems
Depression
No 28 (70.0)
Yes 12 (30.0)
Anxiety
No 23 (57.5)
Yes 17 (42.5)
Sleep disturbance
No 22 (55.0)
Yes 18 (45.0)
Values are presented as number (%) unless otherwise indicated. NHL includes dif-fuse large B cell lymphoma (n = 7), high-grade B cell lymphoma (n = 1), Burkittlymphoma (n = 1), mantle cell lymphoma (n = 3), and follicular lymphoma (n = 2).CNS indicates central nervous system.* Some patients received more than 1 treatment.
Figure 1. Distribution of depression, anxiety, and neurocognitive difficulties at tim
J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43 37
were on antidepressant medications, 12 (30%) were on anxio-lytic medications, and 18 (45%) were prescribed medicationsfor sleep disturbance.
Psychiatric and Cognitive Outcomes after CAR T Cell TherapyAs demonstrated in Figure 1, at the time of questionnaire
completion, 8 (20%) patients reported clinically meaningfuldepression or anxiety (PROMIS T score >55) and at least 1 cog-nitive difficulty, 4 (10%) reported depression or anxiety but nocognitive difficulties, and 7 (17.5%) reported cognitive difficul-ties with no depression or anxiety. Twenty-one (52.5%)patients reported no neuropsychiatric symptoms.
At the time of questionnaire completion, 10 (25%) patientsreported being on medications for depression, 8 (20%)reported being on anxiolytics, and 6 (15%) reported being onmedications for sleep (Table 2). The use of medications fordepression and sleep (as per patients’ report) was statisticallysignificantly lower at the time of questionnaire completioncompared with immediately before CAR T cell therapy (P = .03,P = .007 respectively), whereas the use of anxiolytic medica-tions was not statistically significantly different (P = .44).
Fifteen (37.5%) patients reported 1 or more cognitive diffi-culties. Fourteen (35%) of the patients reported having diffi-culty with memory, 12 (30%) reported difficulty finding words,9 (22.5%) reported difficulty with concentration, and 5 (12.5%)reported difficulty solving problems. Four (10%) patientsreported experiencing all 4 cognitive symptoms.
PROMIS OutcomesPROMIS outcome data (Table 2; Supplementary Figure S1)
demonstrate that mean global mental health, global physicalhealth, social function, anxiety, fatigue, pain, and sleep distur-bance of the study cohort did not clinically meaningfully differfrom that of the general population. However, 5 patients(12.5%) scored �60 in anxiety and/or depression and 7 patients(17.5%) scored �40 in global mental health, indicating at least1 standard deviation worse than the general population mean.
e of questionnaire completion. Calculation based on PROMIS T score �55.
Table 2Self-Reported Outcomes 1 to 5 Years after CAR T Cell Therapy
Patient-Reported Outcomes Value
Neurocognitive difficulties since CAR T cell therapy
Difficulty concentrating 9 (22.5)
Difficulty with word finding 12 (30.0)
Difficulty with memory 14 (35.0)
Difficulty solving problems 5 (12.5)
Number of cognitive complaints
0 25 (62.5)
1 1 (2.5)
2 7 (17.5)
3 3 (7.5)
4 4 (10.0)
Taking medications for
Depression 1 (2.5)
Anxiety 8 (20.0)
Sleep disturbance 6 (15.0)
Fatigue 1 (2.5)
PROMIS measures (T scores), mean (SD)
Global mental health 48.9 (9.9)
Global physical health 48.8 (10.4)
Ability to participate in social roles and activities 50.9 (10.4)
Anxiety 48.9 (9.0)
Depression 46.3 (8.0)
Sleep disturbance 49.5 (8.3)
Fatigue 48.4 (10.1)
Pain 48.8 (9.3)
Physical function 48.0 (9.6)
Values are presented as number (%) unless otherwise indicated.
38 J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43
Risk Factors for Neuropsychiatric OutcomesUnivariate analyses of potential risk factors for neuropsychi-
atric outcomes after CAR T cell therapy are shown in Tables 3and 4, as well as Supplementary Tables S1 and S2. Younger agewas found to be associated with worse PROMIS global mentalscore (P = .02) and worse PROMIS anxiety (P = .001) and depres-sion scores (P = .01). Anxiety pre-CAR T was associated withPROMIS anxiety post-CAR T (P = .001), but depression pre-CAR Twas not associated with PROMIS depression post-CAR T(P = .60). There was a statistically significant associationbetween pre-CAR T depression and cognitive difficulties (anyversus none) (odds ratio = 6.00, P = .02), and a suggestive associ-ation between neurotoxicity grades 2 to 4 and cognitive difficul-ties (odds ratio = 3.62, P = .07). Longer time since CAR T celltherapy was associated with worse global mental score(P = .04). Inability to work due to health issues was associatedwith worse PROMIS global physical health score (P = .001) (Sup-plementary Table S3), whereas unemployment not due tohealth issues was associated with better PROMIS anxiety score(P = .04) (Supplementary Table S1). Race (white versus others)was not found to be significantly associated with PROMIS globalmental score (Table 3), PROMIS anxiety score (SupplementaryTable S1), or PROMIS depression score (Supplementary TableS2). However, race might have been associated with reportedcognitive status, as 15 of 33 white patients (45%) reported atleast 1 cognitive difficulty, whereas none of the 7 nonwhitepatients reported cognitive difficulties (P = .03) (Table 4). Therewas no association between disease status at the time of ques-tionnaire completion and patient-reported neuropsychiatricoutcomes, and there was no association between allogeneicHCT before or after CAR T cell therapy and reported neuropsy-chiatric outcomes (Tables 3 and 4).
Multivariate analysis suggested an association between age(P = .03) and time of assessment after treatment (P = .08) withPROMIS global mental health score (Table 3), as well as anassociation between pre-CAR T depression (P = .02) and acuteneurotoxicity (grades 2 to 4 versus 0 to 1; P = .08) with cogni-tive difficulties after treatment (any versus none) (Table 4).
As shown in Figure 2, having more cognitive difficulties wasassociated with having worse global mental health (P = .0001)and global physical health (P = .01). Similarly, worse scores forpain interference, sleep disturbance, fatigue, depression, anxi-ety, physical function, and social function were associated withmore cognitive difficulties (P = .007, P = .0003, P = .00006, P = .01,P = .0007, P = .003, P = .0004, respectively).
Correlation analysis of PROMIS outcomes (Figure 3) showsstrong positive correlations (r � 0.6) between physical andsocial function, global mental and social function, global physi-cal function and physical function, anxiety and depression,sleep disturbance and fatigue, and fatigue and pain. There wasa very strong inverse correlation (r � �0.8) between fatigueand social function, as well as strong inverse correlations (r ��0.6) between fatigue and physical function, pain and globalphysical function, pain and social function, anxiety and globalmental function, fatigue and global mental function, and sleepdisturbance and global mental function.
DISCUSSIONCD19-targeted CAR T cell therapy has revolutionized the
treatment of relapsed/refractory B cell malignancies, with anunprecedented response rate in this heavily pretreated popu-lation. However, data regarding long-term effects after thisnovel therapy are still scarce. In this study, we examine self-reported long-term neuropsychiatric status and other patient-reported outcomes of patients after CAR T cell therapy.
Patients in our study received a median of 5 lines of therapybefore CAR T cells, including HCT in 11 patients (27.5%), and 12patients (30%) received allogeneic HCT after their CAR T celltherapy. The high rate of prior or subsequent treatment andlack of baseline PRO data before CAR T cell therapy prevents usfrom determining the direct impact of CAR T cell therapy onoutcomes. However, overall, our data demonstrate that themean self-reported neuropsychiatric status of long-term survi-vors after CD-19 CAR T cell therapy was not clinically meaning-fully different from the general US population.
Cella et al. [25] suggested PROMIS T score thresholds to dif-ferentiate severity levels for pain, fatigue, anxiety, and depres-sion in patients with cancer, and our outcomes fell within thedesignated “normal” range for patients with cancer. Jensenet al. [24] proposed reference mean T scores for PROMIS meas-ures in patients with cancer 6 to 13 months after initial diag-nosis, and our study cohort’s mean T scores are equivalent toor slightly better than those values—for example, fatigue (48.4versus 52.2), pain (48.8 versus 52.4), and physical function(48.8 versus 44.8). The authors included a subset of patientswith NHL, and compared with that group, our study cohortdemonstrated slightly better mean T scores in depression(46.3 versus 49.3), fatigue (48.4 versus 52.2), and pain (48.8versus 51.9), but the differences are below the 5-point thresh-old we consider a clinically meaningful difference. Despitethese overall mean scores, nearly 1 in 5 patients in our cohortscored at least 1 standard deviation lower than the generaland cancer populations’ means in global mental health, indi-cating that a significant number of patients would likely bene-fit from additional mental health services in the yearsfollowing CAR T therapy.
Table 3Risk Factor Regression Analyses for PROMIS Global Mental Health T Score
Variable Coefficient Standard Error P Value
Univariate analysis*
Demographics
Age at time of CAR T therapy 0.30 0.12 .02
Sex (male versus female) �0.01 3.57 1.00
Race (white versus other) 1.59 3.91 .69
Marital status (nonmarried versus married) �1.38 3.61 .70
Employment status (not working, but not due to health versus working) 3.50 3.62 .34
Employment status (unable to work due to health issues versus working) �1.70 3.67 .65
Medical factors
Diagnosis (CLLversus ALL)
6.51 3.63 .08
Diagnosis (NHLversus ALL)
�0.33 3.63 .93
No. of prior linesof therapy
�0.41 0.84 .63
CNS disease involvement (yes versus no) �3.82 4.19 .37
CNS-directed chemotherapy before CAR T(yes versus no)
�3.73 3.17 .25
CRS (2-4 versus 0-1) �3.59 2.94 .23
Neurotoxicity (2-4 versus 0-1) �1.86 3.12 .55
Allogeneic HCT before CAR T (versus no allogeneic HCT at any time) �4.12 3.60 .26
Allogeneic HCT after CAR T (versus no allogeneic HCT at any time) �5.14 3.57 .16
Remission status (remission versus not in remission at time of questionnaire completion) 0.14 4.11 .97
Assessment year after CAR T cells �2.65 1.28 .04
Psychiatric problems before CAR T (yes versus no)
Depressiony �6.25 3.20 .06
Anxiety �3.09 3.14 .33
Insomnia �0.28 3.09 .93
Substance use disorder 6.21 5.76 .29
Multivariate analysisz,x
Age at time of CAR T therapy 0.27 0.12 .03
Assessment year after CAR T cells �2.23 1.22 .08
* Adjusted for depression before CAR T therapy.y Not adjusted for depression before CAR T therapy.z Multivariate analyses were performed on selected outcomes using stepwise selection, with a P value threshold of less than .10 for model entry and exit. All varia-
bles in the univariate analyses were included in the multivariable selection process.x Adjusted for depression prior to CAR-T therapy.Adjusted of the multivariate analysis for allogeneic HCT before or after CAR-T cell therapy did not change the results.
J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43 39
Our findings demonstrate similar PROMIS global physicalhealth among patients at 1 to 5 years after CAR T cell therapy(mean T score 48.8) and the general population. This is consis-tent with prior studies demonstrating similar PROMIS globalphysical health scores in survivors of hematologic cancers(mean T score 48.5) [44], older adults with cancer (mean Tscore 48) [45], and long-term survivors after allogeneic orautologous HCT (median T scores 50.8 and 47.7, respectively)[26]. Similarly, PROMIS global mental health in our cohort(mean T score 48.9) was similar to the general population orother cancer patient population. In comparison, mean PROMISglobal mental health T scores of 51.7 and 51 were found inhematologic cancer survivors and in older adults with cancer,respectively [44,45], and Shaw et al. [26] found a medianPROMIS global mental T score of 50.8 among long-term trans-plant survivors. Furthermore, allogeneic HCT before or afterCAR T cell therapy did not seem to affect the PROMIS globalmental score of patients in our cohort.
Older age was statistically significantly associated with bet-ter global mental health and less anxiety and depression,which is consistent with prior studies that demonstratedyounger age as a risk factor for worse mental health in patients
with cancer [24,26,44,46]. In addition, we found that havingmore cognitive difficulties was associated with worse globalmental and physical health, as well as more pain, fatigue, sleepdisturbance, depression, and anxiety. This finding is consistentwith Reid-Arndt et al. [47], who demonstrated an associationbetween worse cognitive function and poorer quality of life inpatients with breast cancer.
Although no intrapatient longitudinal data are currently avail-able in our cohort, our data suggest worse global mental healthlater after treatment. A potential explanation to this finding is thatearly after CAR T cell therapy, patients may be relieved to be alivegiven their previously refractory cancer. However, over time, sur-vival may hold less psychological weight as patients adjust back tolife and need to cope with ongoing symptoms and other psycho-social stressors. In the future, it will be important to examine lon-gitudinal data for individual patients.
Of the patients in our cohort, 37.5% reported at least 1 cogni-tive difficulty. Similar cognitive difficulties (memory, attention,concentration) are known to arise after chemotherapy and HCT,with rates of impairment varying between 16% and 50% amongcancer survivors assessed between 6 months and 10 years aftertreatment [47-50]. In an HCT survivor population 5 years after
Table 4Risk Factor Regression Analyses for Cognitive Difficulties (Any versus None)
Variable Odds Ratio 95% Confidence Interval P Value
Univariate analysis
Demographics
Age at time of CAR T therapy 0.97 0.92-1.03 .34
Sex (male versus female) 0.34 0.09-1.28 .11
Race (white versus other) infinite infinite .03*
Marital status (nonmarried versus married) 2.62 0.58-12.76 .21
Employment status (not working, but not due to health versus working) 0.32 0.04-1.74 .21
Employment status (unable to work due to health issues versus working) 1.43 0.32-6.52 .64
Medical factors
Diagnosis (CLL versus ALL) 0.44 0.08-2.25 .32
Diagnosis (NHL versus ALL) 0.90 0.18-4.52 .90
No. of prior lines of therapy 0.91 0.63-1.29 .60
CNS disease involvement (yes versus no) 4.18 0.71-33.66 .13
CNS-directed chemotherapy before CAR T (yes versus no) 2.25 0.59-8.86 .23
CRS (2-4 versus 0-1) 2.17 0.59-8.72 .25
Neurotoxicity (2-4 versus 0-1) 3.62 0.94-15.02 .07
Allogeneic HCT before CAR T (versus no allogeneic HCT at any time) 2.00 0.41-10.16 .39
Allogeneic HCT after CAR T (versus no allogeneic HCT at any time) 1.71 0.36-8.4 .50
Remission status (remission versus not in remission at time of questionnaire completion) 0.23 0.01-1.53 .19
Assessment year after CAR T cells 0.97 0.54-1.74 .91
Psychiatric problems before CAR T (yes versus no)
Depression 6.00 1.45-28.93 .02
Anxiety 2.03 0.56-7.72 .29
Insomnia 1.71 0.47-6.42 .41
Multivariate analysisy
Neurotoxicity (2-4 versus 0-1) 3.83 0.88-18.8 .08
Depression pre-CAR T 6.28 1.41-33.7 .02
* Due to a 0 cell (0 nonwhite patients with cognitive difficulties), Fisher exact test was used to calculate P values.y Multivariate analyses were performed on selected outcomes using stepwise selection, with a P value threshold of less than .10 for model entry and exit. All varia-
bles in the univariate analyses were included in the multivariable selection process.Adjusted of the multivariate analysis for allogeneic HCT before or after CAR-T cell therapy did not change the results.
40 J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43
transplant, 41.5% had at least mild impairment on neuropsycho-logic function [49]. It is notable that in our cohort, age, number ofprior therapies, allogeneic HCT before or after CAR T cell therapy,and presence or severity of CRS were not associated with self-reported cognitive difficulties. However, there was a trend towardassociation between early neurotoxicity and reported cognitivedifficulties. Similarly, delirium immediately following hematopoi-etic stem cell transplant has been shown to be associated withsubjective reports of worse memory and executive functioning6 months and 1 year after HCT [51]. Larger studies of patientsreceiving CAR T cell therapy are necessary to determine if there issignificant association between acute neurotoxicity after CAR Tcell therapy and long-term cognitive impairment. Although acuteneurotoxicity is a well-documented adverse event of CAR T celltherapy, only limited data are available regarding its risk factorsand pathophysiology [15,52,53]. Better understanding of acuteneurotoxicity after CAR T cell administration is needed to under-stand the potential association between acute neurotoxicity andlong-term neurocognitive outcomes after CAR T cell therapy.
Our data demonstrate a potential association between raceand patient-reported cognitive difficulties, as 45% of whitepatients reported at least 1 cognitive difficulty, whereas noneof the nonwhite patients reported any cognitive difficulties. Itcould be that the difference in reported cognitive status isderived from cultural differences, but a larger cohort is neededto validate those findings. In addition, as there is some evi-dence that self-reported cognitive impairment may not corre-late with objective cognitive function [54,55], it will be usefulto include objective cognitive testing in future studies.
Correlation analysis of PROMIS outcomes (Figure 2) con-firms strong associations between social function and physicaland mental health, as well as a strong inverse associationbetween social function and fatigue, pain, and sleep distur-bance. In addition, the findings highlight the inverse associa-tion between fatigue and global mental and physical health.Fatigue is one of the most common and distressing symptomsfor patients with cancer, and these correlations further arguefor the importance of providing cancer survivors access totreatments for fatigue [56-58].
Although our results suggest overall no difference in meanmental health in patients after CAR T cell therapy comparedwith the mean of the general population, a subset of patientshad clinically meaningful mental (30%) issues (PROMIS T scoregreater than half of the standard deviation) or cognitive (17.5%)impairment. Our regression analyses suggest that younger age,longer time since treatment, depression pre-CAR T, and acuteneurotoxicity are potential risk factors for these negative out-comes. This demonstrates the need for longitudinal clinical mon-itoring of survivors’ neuropsychiatric symptoms, particularlyamong younger patients, and connecting them with mentalhealth and neurologic services as well as cognitive rehabilitationservices [44,59]. Drawing from our multivariate analyses, futurestudies should examine whether preventing or treating depres-sion and neurotoxicity during CAR T cell therapy can help pre-vent long-term neuropsychiatric problems.
Limitations of our study include sampling bias (includingpatients who survived at least 1 year after CAR T cell therapy),small sample size, lack of standardized neuropsychiatric and
Figure 2. Association between cognitive difficulties and PROMIS outcomes.
Figure 3. Correlation analysis of PROMIS scores.
J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43 41
42 J. Ruark et al. / Biol Blood Marrow Transplant 26 (2020) 34�43
cognitive assessments, lack of baseline PRO data at time of treat-ment, and variability in time points when data were collectedpost-treatment (between 1 and 5 years) with no intrapatient lon-gitudinal assessment after treatment. As pre-CAR T data werederived from medical records and post-CAR T data were derivedfrom PROs, we cannot directly compare neuropsychiatric symp-toms before and after treatment. Future studies comparingPROMIS measures before and after CAR T cell therapy will be nec-essary to understand better the direct impact of CAR T cell therapyon neuropsychiatric outcomes. In addition, it will be useful to col-lect longitudinal PRO data to understand the trajectory of neuro-psychiatric outcomes over time. Our study did not includedomains of spirituality and religiosity. As CAR T cell therapy isbeing given worldwide, future studies may include these domainsto understand better how cultural, spiritual, and religious differen-ces throughout the world potentially affect neuropsychiatric out-come after CAR T cell therapy.
In conclusion, despite acute neurotoxicity, our findings sug-gest overall good neuropsychiatric outcomes in long-term survi-vors after CAR T cell therapy. However, a subset of patients mayexperience psychiatric symptoms or cognitive impairment(which may be related to CAR T cell therapy or other treatmentspatients have been exposed to), and it is important to identifythose patients to assist with intervention strategies.
ACKNOWLEDGMENTSThe authors thank the patients who participated in the clin-
ical trial and answered the questionnaire, the members of theresearch and clinical staff at the FHCRC/Seattle Cancer CareAlliance, and referring physicians for their care of our patientsafter CAR T cell therapy.
Financial disclosure: This study was supported by theNational Institutes of Health (NIH) National Cancer Institute(grants R01 CA136551 and P30 CA15704); NIH National Insti-tute of Diabetes and Digestive and Kidney Diseases (grant P30DK56465); NIH National Heart, Lung, and Blood Institutefunded National Gene Vector Biorepository at Indiana Univer-sity (contract 75N92019D00018); Life Science Discovery Fund;Bezos Family; FHCRC Immunotherapy Integrated ResearchCenter; and Juno Therapeutics/Celgene, Inc.
Conflict of interest statement: J.R., E.M., N.C., A.C., E.D.B., V.W., J.V., B.E.S., K.F., S.J.L., J.R.F., and M.B. declare no competingfinancial interests. C.J.T. receives research funding from JunoTherapeutics and Nektar Therapeutics; has served on the advi-sory board of Precision Biosciences, Eureka Therapeutics, Cari-bou Biosciences, T-CURX, Nektar Therapeutics, Allogene, Kite/Gilead, Novartis, and Humanigen; and has stock/options inPrecision Biosciences, Eureka Therapeutics, and Caribou Bio-sciences. D.G.M. has received research funding from KitePharma (a Gilead Company), Juno Therapeutics (a Celgene/Bristol-Myers Squibb Company), and Celgene and has servedon advisory boards for Kite Pharma, Gilead, Genentech, Novar-tis, and Eureka Therapeutics.
SUPPLEMENTARY MATERIALSSupplementary data related to this article can be found
online at doi:10.1016/j.bbmt.2019.09.037.
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